Exploratory Data Analysis of SAD, MAD, and Renal Studies

Study Descriptions

Single Ascending Dose (SAD) Study

• The SAD study was conducted in a healthy volunteer population.
• The study consisted of 7 cohorts: placebo, 5, 10, 25, 100, 150, and 200 mg administered as an oral suspension.
• A total of 5 subjects were enrolled in each cohort.
• Plasma samples at were collected at 0.5, 1.0, 1.5, 2, 3, 4, 6, 12, 24, 48, 72, 96 hours post-dose.

Multiple Ascending Dose (MAD) Study

• The MAD study was conducted in a healthy volunteer population.
• Simulin was administered as an oral suspension, twice daily (BID) for 6 days.
• The study included 6 cohorts: placebo, 10, 25, 50, 75, and 100 mg.
• A total of 10 subjects were enrolled in each cohort.
• Plasma samples were collected at 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Day 1; pre-dose on Day 2; 1-4 hours post-dose on Days 3 to 6; and 1, 2, 4, 6, 12, 24, 36, 60, and 84 hours post-dose on Day 6.

Renal Impairment Study

• The renal study was conducted in healthy volunteers and subjects with mild, moderate, or severe renal impairment.
• Simulin was administered as a 25 mg oral tablet, twice daily (BID) for 6 days The study included 4 cohorts: normal renal function, mild renal impairment, moderate renal impairment, and severe renal impairment
• A total of 10 subjects were enrolled in each cohort
• Plasma samples were collected at 1, 2, 4, 6, and 12 hours after the first dose; and at 1, 2, 4, 6, 12, 24, 36, 60, and 84 hours after the last dose.

EDA Strategy

• Tasks and Questions
  • Examine the data counts for each study.
    • Do the number of observations in each cohort match the protocol?
    • Do the number of dose administrations match the protocol?
  • Examine the distributions of continuous covariates.
    • Is the data sufficient for the planned covariate analyses?
    • Are any of the continuous covariates highly correlated?
    • Are there any obvious outliers?
  • Examine the distributions of categorical covariates.
    • Is the data sufficient for the planned covariate analyses?
    • Are any of the categorical and continuous covariates highly correlated?
  • Examine the concentration-time plots for each study/cohort.
    • What compartmental models might be appropriate?
    • Are there any unusual absorption phenomena to be accounted for (absorption lag, double peaks)?
    • Are there any obvious outliers?
  • Examine dose-normalized concentration-time plots for each study/cohort.
    • Is there evidence of non-linear kinetics?
  • Examine concentration-time plots stratified/colored by important covariates.
    • Is there evidence of a covariate effect on concentration?
  • Examine individual concentration-time plots.
    • Are there any outliers or evidence of other data issues?

Data Disposition

Data Counts by Dose

Data Counts by Renal Function

Covariate Distributions

Continuous Covariates

Continuous Covariate Pairs Plot

Categorical Covariates

Body Weight and eGFR by Sex

Body Weight and eGFR by Renal Function Category

Concentration vs Time Plots

Semi-log Concentration vs Time Plots

Absorption Phase of SAD study

Dose-normalized Concentration vs Time Plots

Concentration vs Time by Renal Function Category

Concentration vs Time by Formulation

Individual Concentration vs Time Plots

SAD Study

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MAD Study

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Renal Study

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